Comprehensive genetic definition of susceptibility to toxic side effects of irinotecan in mice.

e13566 Background: Adverse drug reactions (ADRs) are major obstacles of cancer therapy, but causes of their individual predisposition remain largely unknown. Irinotecan, an effective anti-cancer drug, causes frequent severe ADRs and their genetics has been a major paradigm for pharmacogenetics of anti-cancer drugs. UGT1A1 (UDP-glucuronosyltransferase) inactivates irinotecan’s cytotoxic metabolite SN-38. UGT1A1*28/*28 homozygous patients have low expression of UGT1A1, high plasma SN-38 levels, and in 50% develop grade 3-4 neutropenia. However, ±75% of such irinotecan-induced neutropenias occur in UGT1A1*1/*1 or UGT1A1*1/*28 patients independently of SN-38 levels. The causes of this majority of irinotecan-ADRs are unknown, suggesting effects of additional genes. Methods: To search for such additional genes we used a phenotype-driven linkage analysis of irinotecan-ADRs in mice. Such analysis, in contrast to candidate-gene studies, can detect genes of any functional class that control irinotecan-ADRs. We analyzed genetics of body-weight loss, mortality, myelotoxicity, and diarrhea. We compared kinetics of plasma levels of irinotecan and its metabolites SN-38 and SN-38G in ADR-susceptible and resistant strains. Results: We detected and mapped 11 new Adri (Adverse drug reaction irinotecan) genes controlling irinotecan-ADR susceptibility. They are distinct from the known irinotecan PK and PD genes and DNA-repair genes, do not affect SN-38 levels, determine cumulatively individual ADR-susceptibility, but not irinotecan tumor response or ADRs by other drugs. Adri genes affect either myelotoxicity or diarrhea. In the pathogenic pathway controlling diarrhea, Adri1 determines its incidence and Adri5 mortality. Conclusions: Irinotecan-ADR susceptibility is controlled in mice by multiple tissue specific Adri-genes. Unlike in UGT1A1*28/*28 homozygotes, causes of increased irinotecan toxicity in mice and likely also in most humans are not high systemic SN-38 levels, but probably increased sensitivity of normal tissues. Such ADRs may require a different clinical management. Adri genes likely represent novel regulators of local irinotecan effects and potential new pharmacological targets.